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Title: Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Roche
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1051876
Resource Type:
Journal Article
Journal Name:
Proc. Natl. Acad. Sci. USA
Additional Journal Information:
Journal Volume: 109; Journal Issue: (29) ; 07, 2012
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Graves, Bradford, Thompson, Thelma, Xia, Mingxuan, Janson, Cheryl, Lukacs, Christine, Deo, Dayanand, Di Lello, Paola, Fry, David, Garvie, Colin, Huang, Kuo-Sen, Gao, Lin, Tovar, Christian, Lovey, Allen, Wanner, Jutta, and Vassilev, Lyubomir T. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. United States: N. p., 2019. Web. doi:10.1073/pnas.1203789109.
Graves, Bradford, Thompson, Thelma, Xia, Mingxuan, Janson, Cheryl, Lukacs, Christine, Deo, Dayanand, Di Lello, Paola, Fry, David, Garvie, Colin, Huang, Kuo-Sen, Gao, Lin, Tovar, Christian, Lovey, Allen, Wanner, Jutta, & Vassilev, Lyubomir T. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. United States. doi:10.1073/pnas.1203789109.
Graves, Bradford, Thompson, Thelma, Xia, Mingxuan, Janson, Cheryl, Lukacs, Christine, Deo, Dayanand, Di Lello, Paola, Fry, David, Garvie, Colin, Huang, Kuo-Sen, Gao, Lin, Tovar, Christian, Lovey, Allen, Wanner, Jutta, and Vassilev, Lyubomir T. Tue . "Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization". United States. doi:10.1073/pnas.1203789109.
@article{osti_1051876,
title = {Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization},
author = {Graves, Bradford and Thompson, Thelma and Xia, Mingxuan and Janson, Cheryl and Lukacs, Christine and Deo, Dayanand and Di Lello, Paola and Fry, David and Garvie, Colin and Huang, Kuo-Sen and Gao, Lin and Tovar, Christian and Lovey, Allen and Wanner, Jutta and Vassilev, Lyubomir T.},
abstractNote = {},
doi = {10.1073/pnas.1203789109},
journal = {Proc. Natl. Acad. Sci. USA},
number = (29) ; 07, 2012,
volume = 109,
place = {United States},
year = {2019},
month = {2}
}

Works referenced in this record:

p53 Activation by Small Molecules:  Application in Oncology
journal, July 2005

  • Vassilev, Lyubomir T.
  • Journal of Medicinal Chemistry, Vol. 48, Issue 14
  • DOI: 10.1021/jm058174k

MDM2 Promotes Ubiquitination and Degradation of MDMX
journal, August 2003


Hdmx Modulates the Outcome of P53 Activation in Human Tumor Cells
journal, August 2006

  • Wade, Mark; Wong, Ee Tsin; Tang, Mengjia
  • Journal of Biological Chemistry, Vol. 281, Issue 44
  • DOI: 10.1074/jbc.M605405200

MdmX Protein Is Essential for Mdm2 Protein-mediated p53 Polyubiquitination
journal, May 2011

  • Wang, Xinjiang; Wang, Junru; Jiang, Xuejun
  • Journal of Biological Chemistry, Vol. 286, Issue 27
  • DOI: 10.1074/jbc.M110.213868

The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo
journal, July 2011

  • Huang, L.; Yan, Z.; Liao, X.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 29
  • DOI: 10.1073/pnas.1102309108

Awakening guardian angels: drugging the p53 pathway
journal, December 2009

  • Brown, Christopher J.; Lain, Sonia; Verma, Chandra S.
  • Nature Reviews Cancer, Vol. 9, Issue 12
  • DOI: 10.1038/nrc2763

Amplification of Mdmx (or Mdm4) Directly Contributes to Tumor Formation by Inhibiting p53 Tumor Suppressor Activity
journal, June 2004


Inhibitors of MDM2 and MDMX: a structural perspective
journal, September 2009

  • Riedinger, Christiane; McDonnell, James M.
  • Future Medicinal Chemistry, Vol. 1, Issue 6
  • DOI: 10.4155/fmc.09.75

Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
journal, November 1996


The p53 pathway: positive and negative feedback loops
journal, April 2005


Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
journal, March 2006

  • Marine, J-C; Francoz, S.; Maetens, M.
  • Cell Death & Differentiation, Vol. 13, Issue 6
  • DOI: 10.1038/sj.cdd.4401912

Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans
journal, January 2008

  • Linke, K.; Mace, P. D.; Smith, C. A.
  • Cell Death & Differentiation, Vol. 15, Issue 5
  • DOI: 10.1038/sj.cdd.4402309

Levels of HdmX Expression Dictate the Sensitivity of Normal and Transformed Cells to Nutlin-3
journal, March 2006


Molecular Basis for the Inhibition of p53 by Mdmx
journal, October 2007

  • Popowicz, Grzegorz M.; Czarna, Anna; Rothweiler, Ulli
  • Cell Cycle, Vol. 6, Issue 19
  • DOI: 10.4161/cc.6.19.4740

Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain
journal, August 2008

  • Popowicz, Grzegorz; Czarna, Anna; Holak, Tad
  • Cell Cycle, Vol. 7, Issue 15
  • DOI: 10.4161/cc.6365

A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
journal, November 2010


Identification and Characterization of the First Small Molecule Inhibitor of MDMX
journal, January 2010

  • Reed, Damon; Shen, Ying; Shelat, Anang A.
  • Journal of Biological Chemistry, Vol. 285, Issue 14
  • DOI: 10.1074/jbc.M109.056747

Mdmx as an essential regulator of p53 activity
journal, June 2005

  • Marine, Jean-Christophe; Jochemsen, Aart G.
  • Biochemical and Biophysical Research Communications, Vol. 331, Issue 3
  • DOI: 10.1016/j.bbrc.2005.03.151

Functions of MDMX in the Modulation of the p53-Response
journal, January 2011

  • Lenos, Kristiaan; Jochemsen, Aart G.
  • Journal of Biomedicine and Biotechnology, Vol. 2011
  • DOI: 10.1155/2011/876173

Hdmx Protein Stability Is Regulated by the Ubiquitin Ligase Activity of Mdm2
journal, July 2003

  • de Graaf, Petra; Little, Natalie A.; Ramos, Yolande F. M.
  • Journal of Biological Chemistry, Vol. 278, Issue 40
  • DOI: 10.1074/jbc.M213034200

Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes
journal, January 2009

  • Kallen, Joerg; Goepfert, Arnaud; Blechschmidt, Anke
  • Journal of Biological Chemistry, Vol. 284, Issue 13
  • DOI: 10.1074/jbc.M809096200

Potent and Orally Active Small-Molecule Inhibitors of the MDM2−p53 Interaction
journal, December 2009

  • Yu, Shanghai; Qin, Dongguang; Shangary, Sanjeev
  • Journal of Medicinal Chemistry, Vol. 52, Issue 24
  • DOI: 10.1021/jm901400z

Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
journal, December 2006

  • Toledo, Franck; Wahl, Geoffrey M.
  • Nature Reviews Cancer, Vol. 6, Issue 12
  • DOI: 10.1038/nrc2012

Mdm2-mediated ubiquitylation: p53 and beyond
journal, June 2009

  • Marine, J-C; Lozano, G.
  • Cell Death & Differentiation, Vol. 17, Issue 1
  • DOI: 10.1038/cdd.2009.68

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy
journal, January 2006

  • Tovar, C.; Rosinski, J.; Filipovic, Z.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 6
  • DOI: 10.1073/pnas.0507493103

MDM2 inhibitors for cancer therapy
journal, January 2007


Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation
journal, June 2008

  • Xia, Mingxuan; Knezevic, Dejan; Tovar, Christian
  • Cell Cycle, Vol. 7, Issue 11
  • DOI: 10.4161/cc.7.11.5929

Role of Mdm4 in drug sensitivity of breast cancer cells
journal, February 2010


Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?
journal, January 2009


Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition
journal, March 2008

  • Shangary, S.; Qin, D.; McEachern, D.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 10
  • DOI: 10.1073/pnas.0708917105

DNA Damage-induced MDMX Degradation Is Mediated by MDM2
journal, September 2003

  • Kawai, Hidehiko; Wiederschain, Dmitri; Kitao, Hiroyuki
  • Journal of Biological Chemistry, Vol. 278, Issue 46
  • DOI: 10.1074/jbc.M308295200

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation
journal, June 1992


Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
journal, March 2009

  • Pazgier, M.; Liu, M.; Zou, G.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 12
  • DOI: 10.1073/pnas.0900947106

In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
journal, February 2004


The p53 orchestra: Mdm2 and Mdmx set the tone
journal, May 2010


RING Domain-Mediated Interaction Is a Requirement for MDM2's E3 Ligase Activity
journal, July 2007


A Medicinal Chemist’s Guide to Molecular Interactions
journal, July 2010

  • Bissantz, Caterina; Kuhn, Bernd; Stahl, Martin
  • Journal of Medicinal Chemistry, Vol. 53, Issue 14
  • DOI: 10.1021/jm100112j